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1.
Science ; 367(6482): 1147-1151, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32139546

RESUMO

Mycobacterium tuberculosis has an unusual outer membrane that lacks canonical porin proteins for the transport of small solutes to the periplasm. We discovered that 3,3-bis-di(methylsulfonyl)propionamide (3bMP1) inhibits the growth of M. tuberculosis, and resistance to this compound is conferred by mutation within a member of the proline-proline-glutamate (PPE) family, PPE51. Deletion of PPE51 rendered M. tuberculosis cells unable to replicate on propionamide, glucose, or glycerol. Growth was restored upon loss of the mycobacterial cell wall component phthiocerol dimycocerosate. Mutants in other proline-glutamate (PE)/PPE clusters, responsive to magnesium and phosphate, also showed a phthiocerol dimycocerosate-dependent growth compromise upon limitation of the corresponding substrate. Phthiocerol dimycocerosate determined the low permeability of the mycobacterial outer membrane, and the PE/PPE proteins apparently act as solute-specific channels.


Assuntos
Amidas/metabolismo , Proteínas de Bactérias/metabolismo , Membrana Celular/metabolismo , Glucose/metabolismo , Glicerol/metabolismo , Mycobacterium tuberculosis/metabolismo , Proteínas de Bactérias/genética , Transporte Biológico , Permeabilidade da Membrana Celular , Farmacorresistência Bacteriana/genética , Deleção de Genes , Lipídeos/química , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia
2.
J Assoc Physicians India ; 68(3): 59-63, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32138486

RESUMO

Introduction: Doxycycline acts against a broad range of gram-positive, gramnegative and 'atypical' bacteria as well as some protozoan pathogens such as malaria. In this era of increasing multidrug-resistance, recycling of old antimicrobials should be considered and need more focus in this domain of research. We, therefore, aimed to assess the antimicrobial susceptibility patterns of commonly isolated pathogens against doxycycline, azithromycin, cefuroxime, and amoxicillin from common clinical specimens by using laboratory-based diagnostic data from western India. Materials and Methods: The non-interventional retrospective study was conducted on secondary data extracted from multi-center diagnostic laboratory based in Mumbai, India. Susceptibility data of bacteria isolated from blood, urine, pus, and sputum were used in the study and culture positive samples were segregated. Antimicrobial susceptibility status of doxycycline was checked and compared with azithromycin, cefuroxime, and amoxicillin. Chi-square tests of significance were carried out to assess significant differences in susceptibility patterns. Association between variables was considered statistically significant if the p-value was <0.05. Results: Percentage susceptibility of collective bacterial isolates was found to be highest for doxycycline in all four specimens (93.1%). Individual percentage susceptibility was observed to be highest for sputum isolates (97.5%) followed by blood (93.8%), pus (92.7%) and urine (70.0%). The activity of doxycycline was found to be 93.5% for the samples resistant to azithromycin. Doxycycline also showed good susceptibility for the isolates resistant to amoxicillin and cefuroxime which was 75.9% and 64.8%, respectively. Conclusion: Several bacterial isolates from all four sources were found to be susceptible to Doxycycline. It has an important role in the form of a better alternative of major antimicrobial agents like azithromycin, cefuroxime, and amoxicillin against gram-positive cocci. Doxycycline appeared to show better activity against isolates which were resistant to other three antimicrobials.


Assuntos
Antibacterianos/farmacologia , Amoxicilina/farmacologia , Azitromicina/farmacologia , Cefuroxima/farmacologia , Doxiciclina/farmacologia , Índia , Testes de Sensibilidade Microbiana , Estudos Retrospectivos
3.
Prog Chem Org Nat Prod ; 111: 81-153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32114663

RESUMO

Marine-derived fungi play an important role in the search for structurally unique secondary metabolites, some of which show promising pharmacological activities that make them useful leads for drug discovery. Marine natural product research in China in general has made enormous progress in the last two decades as described in this chapter on fungal metabolites. This contribution covers 613 new natural products reported from 2001 to 2017 from marine-derived fungi obtained from algae, sponges, corals, and other marine organisms from Chinese waters. The genera Aspergillus (170 new natural products, 28%) and Penicillium (70 new natural products, 11%) were the main fungal producers of new natural products during the time period covered, whereas sponges (184 new natural products, 30%) were the most abundant source of new natural products, followed by corals (154 new natural products, 25%) and algae (130 new natural products, 21%). Close to 40% of all natural products covered in this contribution displayed various bioactivities. The major bioactivities reported were cytotoxicity against different cancer cell lines, antimicrobial (mainly antibacterial) activity, and antiviral activity, which accounted for 13%, 9%, and 3% of all natural products reported. In terms of structural classes, polyketides (188 new natural products, 31%) play a dominant role, and if prenylated polyketides and nitrogen-containing polyketides (included in meroterpenes and alkaloids in this contribution) are taken into account, their total number even exceeds 50%. Nitrogen-containing compounds including peptides (65 new natural products, 10%) and alkaloids (103 new natural products, 17%) are the second largest group.


Assuntos
Produtos Biológicos/farmacologia , Fungos/química , Policetídeos/farmacologia , Animais , Antozoários/microbiologia , Anti-Infecciosos , Antineoplásicos , Organismos Aquáticos/microbiologia , Aspergillus/química , Produtos Biológicos/química , China , Penicillium/química , Policetídeos/química , Poríferos/microbiologia , Metabolismo Secundário
4.
Orv Hetil ; 161(10): 363-373, 2020 Mar.
Artigo em Húngaro | MEDLINE | ID: mdl-32115992

RESUMO

Retrometabolic drug design combines the structure-activity and structure-metabolism relationships, allowing the effective separation of drug action and side effects. This combination results in significant improvement of the therapeutic index. The main aim is not only to study the metabolism but to build into the drug molecule the desired metabolic route, in addition to the therapeutic activity. There are two basically different approaches to achieve this aim. Both use designed-in metabolism. The 1. chemical drug-targeting systems (CDS) and 2. soft drug, both control the drug targeting and action by strategically designed metabolism. In the case of the soft drugs, we want to rely on hydrolytic enzymes, avoiding the oxidative processes. In the present work, we focus on the clinical successes of the soft drugs designed in our laboratories. In order to show the difference, we briefly present a brain-targeted delivery system, where the originally inactive molecular construct undergoes sequential metabolism to allow specific concentration of the active drug in the brain. Among the soft drugs first we present the highly successful soft corticosteroids. Loteprednol etabonate has been used worldwide for over twenty years, and its use is constantly growing. In addition to the dramatically improved therapeutic index, the specific, serious ophthalmic side effects (elevation of intraocular pressure; glaucoma and cataract formation) were completely eliminated. Similarly designed second generation of soft corticosteroids are also presented, where the soft pharmacophore is structurally unexpected. The most recent soft drug design involves anticholinergics. Sofpironium bromide, a highly effective molecule but without the typical anticholinergic side effects, was first developed to treat hyperhidrosis, an unmet need. Phase III clinical studies were successfully completed and its marketing approval is pending. Since the soft drug design principles, methods and rules are general and specific in nature, a computerized expert system was also developed. Orv Hetil. 2020; 161(10): 363-373.


Assuntos
Sistemas de Liberação de Medicamentos , Desenho de Drogas , Soluções Oftálmicas/farmacologia , Preparações Farmacêuticas/classificação , Corticosteroides , Olho , Glaucoma , Humanos , Soluções Oftálmicas/química
5.
Orv Hetil ; 161(10): 389-395, 2020 Mar.
Artigo em Húngaro | MEDLINE | ID: mdl-32115993

RESUMO

Introduction: The treatment of preeclampsia, which occurs in 3-8% of pregnancies, is not yet resolved. In preeclampsia, NO synthesis is insufficient, which can contribute to hypertension, proteinuria and abnormal vascularization of the placenta. Decreased NO synthesis in the preeclamptic placenta may also be due to a decrease in the affinity of NO synthase for tetrahydrobiopterin (BH4), resulting in BH4 resistance. In recent years, pravastatin has been shown to prevent preeclampsia in animal models and in human studies. One of the known pleiotropic effects of pravastatin is that it increases NO synthase activity. Aim: Description of the effect of pravastatin on BH4-resistant NO synthase activity in the preeclamptic placenta. Method: NO synthase activity in the placental microsome was measured with C14 arginine substrate using healthy (n = 9) and preeclamptic (n = 9) samples. NO synthase activity was measured at 0.02 µM, physiological at 0.20 µM and pharmacological at 50 µM BH4. Results: One of the 9 preeclamptic patients was BH4-resistant; physiologic BH4 concentration did not significantly increase NO synthase activity, whereas healthy placental microsomes showed a mean increase of 60% (p<0.01), and BH4-sensitive preeclamptic specimen showed a 67% (p<0.01) increase. 10 µM pravastatin increased NO synthase activity by 32-38% at each BH4 concentration in healthy, BH4-sensitive and BH4-resistant preeclampsia samples. Conclusion: 10 µM pravastatin increased BH4-resistant placental NO synthase activity to a similar extent as placental physiological BH4 concentration (0.06-0.20 µM) to BH4-sensitive NO synthase activity. The NO synthase activity of BH4-resistant preeclamptic placenta can be increased by pravastatin to physiological level. Orv Hetil. 2020; 161(10): 389-395.


Assuntos
Biopterina/análogos & derivados , Óxido Nítrico Sintase/efeitos dos fármacos , Placenta/metabolismo , Pravastatina/farmacologia , Pré-Eclâmpsia/metabolismo , Feminino , Humanos , Gravidez
6.
Bratisl Lek Listy ; 121(2): 117-121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115963

RESUMO

AIM: The aim of this study is to demonstrate whether fullerenol C60 protects renal injury in sevoflurane­administered rats. METHOD: Rats (n: 24) were randomly divided into four groups: Control (Group C), Fullerenol C60 (Group F), Sevoflurane (Group S), Fullerenol C60-Sevoflurane (Group FS). Thirty minutes before the procedure, Fullerenol C60, 100 mg/kg, was administered intraperitoneally. Sevoflurane (2.3 %) was applied for 3 hours to rats in S and FS groups. Biochemical and histopathological parameters were analyzed in renal tissue samples. Kruskal-Wallis and Mann-Whitney U tests were used in statistical analyzes. RESULTS: Malondialdehyde (MDA) level and catalase (CAT) enzyme activity in Group S were significantly higher than that in all other groups. Paraoxanase (PON) enzyme activity in Group S was significantly lower than in Groups C and FS. The histopathological examination showed that vascular vacuolization and hypertrophy (VVH) and lymphocyte infiltration (LI) were significantly higher in the Group S compared to the Group C. CONCLUSION: Renal histopathology revealed that the administration of Fullerenol C60 prior to sevoflurane inhalation reduced oxidative stress and partially corrected the damage caused by anesthesia. We concluded that Fullerenol C60 has a renal protective effect in rats when administered before sevoflurane anesthesia (Tab. 2, Fig. 4, Ref. 40).


Assuntos
Fulerenos , Rim , Nanopartículas , Animais , Fulerenos/farmacologia , Rim/efeitos dos fármacos , Malondialdeído , Estresse Oxidativo , Ratos , Sevoflurano
7.
Bratisl Lek Listy ; 121(2): 122-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115964

RESUMO

BACKGROUND: Cancer is a major public health problem in many areas of the world. Many anticancer drugs in current clinical use have been isolated from plant species or are based on such substances. Thymol (5-methyl-2-isopropylphenol) is an oxygenated aromatic compound from monoterpene group. It is the main constituent of thyme essential oil and shows antioxidant, antiseptic and antiproliferative properties. The aim of this study is to determine the antiproliferative activity and apoptotic effect of thymol on prostate cancer (PC-3, DU145), breast cancer (MDA-MB-231), and lung cancer (KLN205) cell lines. METHODS: The cancer cells were treated with different concentrations of thymol (100, 200, 400, 600, 800 µM) at 24 h, 48 h and 72 h. The cell viability was investigated by MTT assay and analysis of apoptosis was determined with annexin V assay. RESULTS: The study showed the dose and time-dependent cytotoxic effect of thymol in PC-3, DU145, MDA-MB-231, and KLN205 cancer cell lines. Thymol significantly induced apoptosis in all groups in a dose-dependent manner. Statistical analysis showed a significant difference between thymol­treated cell lines compared to the control (p < 0.001). CONCLUSION: The data in the present study demonstrated that thymol has apoptotic and antiproliferative properties in lung, breast and prostate cancer cell lines. Thymol could serve as a potential therapeutic agent in the future (Fig. 5, Ref. 26).


Assuntos
Apoptose , Fenol , Timol , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Humanos , Masculino , Monoterpenos , Timol/farmacologia
8.
Bratisl Lek Listy ; 121(2): 143-150, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115968

RESUMO

OBJECTIVES: This study was aimed to explore the effects of follistatin on cisplatin-induced renal dysfunction, histopathological changes, apoptosis, inflammation and oxidative damage in rats. BACKGROUND: Follistatin plays an important role in the developmental and regeneration processes of kidney by blocking the actions of activin, which is a member of transforming growth factor-ß superfamily. METHODS: Twenty seven rats were separated into 4 equal groups: Control, Cp (cisplatin, 6 mg/kg, intrapertoneally (ip)), F1 (cisplatin + 1 µg/day follistatin ip for 4 consecutive days) and F4 (cisplatin + 4 µg/day follistatin ip single dose) groups. Renal health was monitored by blood urea nitrogen, serum creatinine and histological analysis. Apoptosis, inflammation and oxidative stress was investigated in kidney tissue. Activin A levels in serum and kidney were evaluated as well. RESULTS: Follistatin administration showed a considerable nephroprotective effect against cisplatin-induced nephrotoxicity by preventing renal functional and structural abnormalities, apoptosis and inflammation. The activin A levels in both serum and kidney were also suppressed by follistatin administration. CONCLUSION: Exogenous follistatin ameliorates acute kidney injury, by blocking activin A. The renoprotective effect of follistatin against cisplatin-induced nephrotoxicity appears to be associated with its anti-inflammatory, antiapoptotic and direct nephroprotective actions (Tab. 1, Fig. 7, Ref. 23).


Assuntos
Lesão Renal Aguda , Cisplatino , Folistatina , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Cisplatino/efeitos adversos , Folistatina/farmacologia , Folistatina/uso terapêutico , Inflamação , Rim , Estresse Oxidativo , Ratos
9.
Bratisl Lek Listy ; 121(3): 211-217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115979

RESUMO

OBJECTIVES: Betanin and copper sulphate have been previously indicated as beneficial agents for ischemia/reperfusion (I/R) as antioxidant compounds in various models. We investigated whether betanin and copper have any protective effects on the heart and lung against I/R injury in rats. METHODS: Spraque-Dawley rats were assigned in groups: Sham (laparotomy only), control (I/R only), betanin treatment (100 mg/kg of betanin administered intraperitoneally (i.p.) 60 minutes before I/R) and copper sulfate treatment group (0.1 mg/kg/day copper sulfate i.p. for 7 days before I/R). Ischemia was induced by clamping the aorta between the left renal artery and aortic bifurcation for 45 minutes. After 48-hour reperfusion, the rats were sacrificed and heart/lung tissues were harvested. Malondialdehyde (MDA), myeloperoxidase (MPO), interleukin 6 (IL-6) levels were determined. Apoptosis was determined via TUNEL assay. RESULTS: MDA, MPO, IL-6 levels and apoptotic cells were significantly increased in the I/R group. In both treatment groups, MDA and MPO levels were decreased. IL-6 was significantly decreased in response to betanin administration in the heart, but not in the lung; copper had no effect in either area. The numbers of apoptotic cells were significantly decreased in both treatment groups. CONCLUSION: Betanin and copper may have protective effects on I/R injury in the heart and lung in rats (Fig. 6, Ref. 39).


Assuntos
Betacianinas , Cobre , Traumatismo por Reperfusão , Animais , Betacianinas/farmacologia , Cobre/farmacologia , Coração/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Malondialdeído , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/prevenção & controle
10.
Bratisl Lek Listy ; 121(3): 225-229, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115981

RESUMO

AIM: Nicotine at high concentrations induces apoptosis in trophoblastic cells through induction of cell cytotoxicity and Reactive Oxygen Species (ROS). Methamphetamine in low dose has pharmaceutical properties. It seems that this components in low dose can protect the trophoblastic cells from nicotine-induced cell death. METHOD: Trophoblastic (JEG-3) cells grown in DMEM culture medium. MTT assay test detected the cell viability and Lactate Dehydrogenase test measured the cells cytotoxicity. Griess reaction was used for NO production analysis. Cell migration traced by wounding technique. Human Cytokine Array Focused 13-plex was also used for analysis of IL-1α, IL-1ß, IL-6, INFγ, and TNFα pre-inflammatory cytokines. RESULTS: Methamphetamine, in very low dose (pM), increased the cell viability and NO production, and decreased cell cytotoxicity, IL-1α, IL-1ß, IL-6, INFγ, and TNFα pre-inflammatory cytokines of JEG-3 cell which were exposed to high dose of nicotine, respectively. Cell migration was enhanced by low dose of methamphetamine in JEG-3 cells. CONCLUSION: Methamphetamine in very low dose suppressed the JEG-3 cell death induced by high dose of nicotine (Fig. 5, Ref. 48) Keywords: methamphetamine, nicotine, cell death, NO.


Assuntos
Dopaminérgicos , Inflamação , Metanfetamina , Trofoblastos , Linhagem Celular Tumoral , Sobrevivência Celular , Dopaminérgicos/farmacologia , Humanos , Inflamação/tratamento farmacológico , Metanfetamina/farmacologia , Nicotina/toxicidade , Trofoblastos/efeitos dos fármacos
11.
Bratisl Lek Listy ; 121(3): 235-241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115983

RESUMO

AIM: Hyperglycemia, oxidative stress and hyperlipidemia are features of diabetes mellitus. Thiamine has beneficial effects on carbohydrate metabolism and it was proposed that this vitamin has antihyperlipidemic and antioxidant effects. Our aim was to investigate the effects of thiamine on oxidative stress and metabolic changes in streptozotocin (STZ) induced diabetic rats. METHOD: Diabetes was induced by a single intraperitoneal injection of STZ. Thiamine (6 mg/kg) was added to drinking water for five weeks. The rats were divided into four groups: control rats; thiamine treated control rats; diabetic rats; thiamine treated diabetic rats. Plasma and tissue malondialdehyde (MDA) levels were measured by high-performance liquid chromatography and spectrophotometry, respectively. Paraoxonase (PON) and arylesterase (AE) activities were measured with spectrophotometric methods, and erythrocyte superoxide dismutase (SOD) and blood glutathione peroxidase (GSH-Px) activities were determined using commercial kits. RESULTS: Thiamine treatment reduced plasma and tissue MDA levels, serum glucose, total cholesterol and triglyceride levels, and increased serum high density lipoprotein- cholesterol and insulin levels, serum PON and AE, erythrocyte SOD and blood GSH-Px activities. CONCLUSION: Thiamine significantly improves oxidative stress and has hyperinsulinemic and antihyperlipidemic effects so we suggest that thiamine might be used as a supportive therapeutic agent in diabetes (Tab. 2, Fig. 3, Ref. 53).


Assuntos
Antioxidantes , Diabetes Mellitus Experimental , Estresse Oxidativo , Tiamina , Animais , Antioxidantes/farmacologia , Glicemia , Malondialdeído , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase , Tiamina/farmacologia
12.
Medicine (Baltimore) ; 99(9): e19232, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32118725

RESUMO

The aim of the study was to systematically characterize the interference of biotin on thyroid function tests and biotin washout periods.Ten healthy adults were recruited with administration of 5 and 10 mg/d biotin for 7 days. Analyte concentrations of thyroid function tests were measured at baseline prior to starting biotin and from 2 hours to 2 days after withdrawal of 5 and 10 mg/d biotin. The outcomes were compared the baseline with the several points after taking biotin at Roche cobas e602, Beckman UniCel DxI 800, and Abbott Architect 2000 immunoassay platforms, respectively.Ingesting 5 or 10 mg/d of biotin for 7 days could produce positive or negative interference among the thyroid function tests at Roche cobas e602 and Beckman UniCel DxI 800 systems, but no interference on Abbott Architect 2000. Interference duration of 5 mg/d biotin for Roche cobas e602 and Beckman UniCel DxI 800 of thyroid function tests lasted for 8 hours, while 10 mg/d biotin interfered with Roche cobas e602 or Beckman UniCel DxI 800 for 1 day or 2 days.This study provides valuable guidance on biotin washout periods at doses common in over-the-counter supplements necessary to avoid false assay results.Trial registration: ChiCTR1800020472.


Assuntos
Biotina/farmacologia , Testes de Função Tireóidea/normas , Complexo Vitamínico B/farmacologia , Administração Oral , Adulto , Biotina/administração & dosagem , Feminino , Voluntários Saudáveis , Humanos , Masculino , Tiroxina/sangue , Tiroxina/efeitos dos fármacos , Tri-Iodotironina/sangue , Tri-Iodotironina/efeitos dos fármacos , Complexo Vitamínico B/administração & dosagem , Adulto Jovem
13.
Tumour Biol ; 42(3): 1010428320909999, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32129155

RESUMO

Cancer is the leading cause of death and exhausts human and economic resources for treatment and protection. Zinc oxide nanoparticles play an effective role in tumor treatment but with some cautions, such as overexpression of cytochrome P450, hepatic overload, and the mammalian target of rapamycin pathway resistance. Although lanthanides have antitumor activity, their use is limited. Therefore, the current study aims to improve the effectiveness of zinc oxide nanoparticle via doping with lanthanides, such as samarium. In vitro study revealed that samarium doped with zinc oxide showed more antitumor activity than the other lanthanides, and the antitumor activity depends on the concentration of samarium in the nanocomposite. The in vivo experiment on mice bearing Ehrlich solid tumor revealed that intramuscular injection of samarium/zinc oxide downregulates the expressions of CXCR4 and PI3K/Akt/mammalian target of rapamycin pathway in respect to Ehrlich solid tumor group. Regarding the apoptotic biomarkers, samarium/zinc oxide upregulates the apoptotic biomarker; Bax accompanied with the mitotic catastrophe which was indicated by cell cycle arrest in G2 phase. Moreover, samarium:zinc oxide nanoparticles exhibited minimum toxicity which was indicated by suppressed activities of cytochrome P450 and hepatic enzymes, including alanine transaminase and aspartate transaminase. In addition, the histopathological finding, as well as immunophenotyping results, appreciated the biochemical finding. Therefore, samarium:zinc oxide might be offered a new approach to improve the effectiveness of zinc oxide nanoparticles along with lower toxic effect. Also, samarium:zinc oxide nanoparticles can be a candidate as a new antitumor compound to detect its mode of action.


Assuntos
Antineoplásicos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Receptores CXCR4/antagonistas & inibidores , Samário/farmacologia , Óxido de Zinco/farmacologia , Animais , Regulação para Baixo , Feminino , Camundongos , Nanopartículas , Receptores CXCR4/genética , Samário/efeitos adversos , Óxido de Zinco/efeitos adversos
14.
Nature ; 579(7798): 260-264, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32132711

RESUMO

The production of pore-forming toxins that disrupt the plasma membrane of host cells is a common virulence strategy for bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA)1-3. It is unclear, however, whether host species possess innate immune mechanisms that can neutralize pore-forming toxins during infection. We previously showed that the autophagy protein ATG16L1 is necessary for protection against MRSA strains encoding α-toxin4-a pore-forming toxin that binds the metalloprotease ADAM10 on the surface of a broad range of target cells and tissues2,5,6. Autophagy typically involves the targeting of cytosolic material to the lysosome for degradation. Here we demonstrate that ATG16L1 and other ATG proteins mediate protection against α-toxin through the release of ADAM10 on exosomes-extracellular vesicles of endosomal origin. Bacterial DNA and CpG DNA induce the secretion of ADAM10-bearing exosomes from human cells as well as in mice. Transferred exosomes protect host cells in vitro by serving as scavengers that can bind multiple toxins, and improve the survival of mice infected with MRSA in vivo. These findings indicate that ATG proteins mediate a previously unknown form of defence in response to infection, facilitating the release of exosomes that serve as decoys for bacterially produced toxins.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Toxinas Bacterianas/metabolismo , Exossomos/metabolismo , Células A549 , Proteína ADAM10/metabolismo , Animais , Toxinas Bacterianas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , DNA Bacteriano/farmacologia , Exossomos/efeitos dos fármacos , Exossomos/ultraestrutura , Feminino , Células HEK293 , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Staphylococcus aureus Resistente à Meticilina/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções Estafilocócicas/mortalidade
15.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(3): 234-241, 2020 Mar 12.
Artigo em Chinês | MEDLINE | ID: mdl-32164095

RESUMO

Objective: To evaluate the use of multiplex PCR amplicon sequencing (mPCR-NGS) technology in detecting gene mutations related to drug resistance of Mycobacterium tuberculosis (MTB) in formalin-fixed paraffin-embedded tissue specimens, and to explore its clinical value in the diagnosis of drug-resistant tuberculosis. Methods: Fifty clinical MTB strains isolated in the Changping District Tuberculosis Control Institute of Beijing from April 2013 to October 2015 with drug susceptibility test (DST) results of rifampicin, isoniazid, ethambutol, streptomycin, ofloxacin, capreomycin, kanamycin and amikacin available were recovered, including 42 drug-resistant strains and 8 drug-sensitive strains. The mPCR-NGS test was established to detect genes related to the 8 anti-tuberculosis drugs according to the previously published studies and databases. Fifty-five paraffin-embedded tissue specimens from drug-resistant tuberculosis patients were collected in the Department of Pathology, Beijing Chest Hospital, Capital Medical University during November 2017 to September 2018. All the specimens showed no less than one mutation in the gene regions related to drug resistance of any of the 4 drugs (rifampicin, isoniazid, ethambutol or fluoroquinolones) by probe melting curve assay. The effectiveness of mPCR-NGS test was evaluated on clinical MTB isolates using phenotypic DST as the reference. Clinical evaluation of mPCR-NGS test on formalin-fixed paraffin-embedded specimens from TB patients was performed using probe melting curve assay as the reference. The sensitivity, specificity and coincidence of mPCR-NGS were analyzed. Results: Using phenotypic DST as the reference, the sensitivities of the mPCR-NGS for detecting drug-resistance of rifampicin, isoniazid, streptomycin, and ethambutol were 95% (38/40), 93% (27/29), 93% (27/29), and 72% (13/18), respectively; and the specificities were 100% (10/10), 95% (20/21), 100% (21/21), and 94% (30/32), respectively. The sensitivities for capreomycin, kanamycin and amikacin were all 100% (2/2, 3/3, 3/3), and the specificities were 98% (47/48), 100% (33/33) and 100% (47/47), respectively. The sensitivity and specificity of ofloxacin were 70% (7/10) and 100% (40/40), respectively. The total coincidence rate for the 8vdrugs was 94%, and the Kappa value was 0.87. The 55 paraffin-embedded tissue specimens included in this study were all tested by probe melting curve assays. Among them 28 were resistant to rifampicin, 37 resistant to isoniazid, 13 resistant to ethambutol, and 17 resistant to fluoroquinolones. Using the probe melting curve assay as the reference, the sensitivities of the mPCR-NGS for detecting resistant to rifampicin, isoniazid, ethambutol, and fluoroquinolones were 100% (28/28), 95% (35/37), 100%, and 100%, respectively; and the specificities were all 100% (42/42, 38/38). The total coincidence rate of the two methods was 99%, and the Kappa value was 0.98. Conclusions: mPCR-NGS showed good sensitivities and specificities in detecting drug-resistant gene mutations both in clinical MTB isolates and paraffin-embedded tissue specimens. mPCR-NGS has the potential to be an accurate and rapid molecular pathological technology for diagnosis of drug-resistant tuberculosis.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Genes Bacterianos , Sequenciamento de Nucleotídeos em Larga Escala , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/genética , Humanos , Testes de Sensibilidade Microbiana , Mutação , Inclusão em Parafina , Sensibilidade e Especificidade
16.
Nihon Yakurigaku Zasshi ; 155(2): 113-119, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115477

RESUMO

Nalmefene (Selincro®), an opioid receptor modulator, is approved in Japan, the European Union, and other countries for reducing alcohol consumption in patients with alcohol dependence. This article reviews the efficacy and safety of as-needed use of nalmefene in the treatment of alcohol dependence, as well as summarizing its pharmacological properties. Ethanol increases the release of endogenous opioids, such as ß-endorphin, a µ-opioid receptor agonist; and dynorphin, a κ-opioid receptor agonist. Preclinical data suggest that nalmefene acts as an antagonist at the µ-opioid receptor and a partial agonist at the κ-opioid receptor, and reduces ethanol self-administration in ethanol-dependent and ethanol-non-dependent rats. Nalmefene counters alcohol-induced dysregulation of the ß-endorphin/µ-opioid receptor and the dynorphin/κ-opioid receptor systems. In a multicenter, randomized, double-blind, phase 3 study of as-needed use of nalmefene combined with psychosocial support in alcohol-dependent Japanese patients with at least high drinking risk level, compared with placebo, nalmefene 10 mg and 20 mg significantly reduced the number of heavy drinking days and total alcohol consumption at week 12. In the 24-week treatment period, treatment-emergent adverse events occurred in ≥5% of patients in either the nalmefene 10 mg or 20 mg group and at least twice as often as in the placebo group were nausea, dizziness, somnolence, vomiting, insomnia, decreased appetite, constipation, malaise, and palpitations. Most adverse events were mild or moderate in severity. In conclusion, as-needed use of nalmefene provides a new concept for the treatment of alcohol dependence: namely, "reduction of alcohol intake".


Assuntos
Consumo de Bebidas Alcoólicas/prevenção & controle , Alcoolismo/tratamento farmacológico , Naltrexona/análogos & derivados , Animais , Ensaios Clínicos Fase III como Assunto , Humanos , Japão , Estudos Multicêntricos como Assunto , Naltrexona/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Receptores Opioides kappa/agonistas , Receptores Opioides mu/antagonistas & inibidores
17.
Nihon Yakurigaku Zasshi ; 155(2): 62-68, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115479

RESUMO

The EDRF discovered in 1986 by Furchgott was later identified as NO by Ignarro. NO was a widely noted gas with diverse functions, having arginine (L-Arg) as a substrate for the NO synthase (NOS). L-Arg and L-citrulline (L-Cit) have long been associated with the urea cycle. L-Cit was produced with NO by the reaction of L-Arg and oxygen. It was shown that administration of L-Arg in animals and humans caused vasodilation and anti-arteriosclerosis effects. Despite the arginine paradox ratio of intracellular arginine concentration to the Km value of NOS gaining widespread attention, advanced arteriosclerosis is known to reduce vascular reactivity towards L-Arg. In recent years, the anti-arteriosclerosis and anti-cell aging effects of the reactive substance citrulline (L-Cit) have been studied. L-Cit and L-Arg combination therapy are starting to be considered in various clinical applications as well.


Assuntos
Envelhecimento/fisiologia , Aterosclerose/prevenção & controle , Óxido Nítrico/fisiologia , Animais , Arginina/farmacologia , Aterosclerose/patologia , Citrulina/farmacologia , Humanos , Óxido Nítrico Sintase , Vasodilatação
18.
Emerg Microbes Infect ; 9(1): 517-519, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32116136

RESUMO

We report a recent (2018) gonorrhoeal urethritis caused by a multidrug-resistant Neisseria gonorrhoeae strain in China. The isolated N. gonorrhoeae strain from a male and female pair expressed high-level resistance to spectinomycin (SPC), azithromycin, and other antibiotics but was sensitive to ceftriaxone. The SPC high-level resistance (MIC = 2048 mg/L) was due to a small deletion in rspE that caused two amino acid changes in ribosomal protein S5.


Assuntos
Farmacorresistência Bacteriana Múltipla , Neisseria gonorrhoeae/efeitos dos fármacos , Espectinomicina/farmacologia , China , Neisseria gonorrhoeae/genética , Neisseria gonorrhoeae/metabolismo , Fenótipo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo
19.
Emerg Microbes Infect ; 9(1): 508-516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32116151

RESUMO

Mobile colistin resistance (mcr) genes represent an emerging challenge. Here we describe a novel mcr gene, mcr-10, on an IncFIA plasmid of an Enterobacter roggenkampii clinical strain. mcr-10 has the highest nucleotide identity (79.69%) with mcr-9 and encodes MCR-10 with 82.93% amino acids identical to MCR-9. mcr-10 confers 4-fold increase in colistin MIC (from 1 to 4 mg/L) when cloned into a colistin-susceptible E. roggenkampii strain. By screening GenBank, mcr-10 was found in various Enterobacteriaceae species of countries in four continents, suggesting that this gene has widely spread. MCR-10 shows 79.04% to 83.67% amino acid identity and highly conserved predicted protein structures with chromosomally encoded MCR-like phosphoethanolamine transferases (designated MCR-B here) of various Buttiauxella species. MCR-10, MCR-9 and MCR-B proteins may, therefore, originate from a common ancestor. mcr-10 was adjacent to a site-specific recombinase-encoding gene and was bracketed by IS903 and may be mobilized by site-specific recombination or composite transposon. Our results indicate that mcr-10 is a novel plasmid-borne colistin resistance gene and warrants immediate monitoring and further studies.


Assuntos
Proteínas de Bactérias/genética , Enterobacteriaceae/genética , Sequência de Aminoácidos , Proteínas de Bactérias/química , Colistina/farmacologia , Bases de Dados Genéticas , Farmacorresistência Bacteriana , Enterobacteriaceae/química , Enterobacteriaceae/efeitos dos fármacos , Modelos Moleculares , Plasmídeos , Estrutura Terciária de Proteína , Análise de Sequência de Proteína
20.
Emerg Microbes Infect ; 9(1): 535-538, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32122270

RESUMO

Worldwide emergence of Salmonella enterica serovar Newport (S. Newport) infection in humans, in parallel with a significant increasing prevalence of antimicrobial resistance (AR), is a serious public health concern. However, the prevalence of S. Newport resistance in China remains largely unknown. A retrospective study of 287 S. Newport clinical isolates collected during 1997-2018 was undertaken for characterization of AR profiles using the micro-dilution assay. We found a recent emergence of colistin resistance in four Chinese clinical isolates, including mcr-1-positive isolates. Importantly, phylogenomic and microbiological investigations indicate multiple independent clonal transmission of colistin-resistant S. Newport isolates of different seafood origins. Our study highlights potential reservoirs for transmission of colistin resistance and suggests that the global food supply chain may facilitate this dissemination.


Assuntos
Colistina/farmacologia , Infecções por Salmonella/microbiologia , Salmonella enterica/isolamento & purificação , Farmacorresistência Bacteriana , Humanos , Salmonella enterica/efeitos dos fármacos
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